Cationic antimicrobial peptides, which are 100 amino acids or less in chain size, are produced in all living species. In mammals, they are primarily associated with mucosal epithelial cells and phagocytic cells. These peptides are produced in large amounts at sites of infection and have a broad spectrum of activity not only against gram negative and positive bacteria but also against fungi, viruses and parasites. Seven years ago, it was reported that co-administration of a cationic peptide (human defensin HNP1-3) with ovalbumin (ova), a nonimmunogenic protein, resulted in enhanced production of ova specific IgG antibodies () suggesting that these peptides possess intrinsic adjuvant properties. We have extended these studies employing much smaller peptides (~15 amino acids in length) and shown that co-instilling protective antigen (PA) of anthrax with small antimicrobial peptides into the nasal cavities of mice resulted in markedly elevated levels of PA-specific protective antibodies in the serum. Interestingly, the cationic peptides induced immune responses that were markedly superior to those induced by the powerful mucosal adjuvant cholera toxin that cannot be developed for use in humans because of its toxicity. No systemic or local pathologic effects were observed in mice immunized with small peptides. Antibodies specific for the cationic peptides, that may block its adjuvant activity if used repeatedly, were not detected. The adjuvanticity of these cationic peptides was associated with massive migration of dendritic cells from sites of instillation to the draining lymph nodes (DLNs) and large scale sequestration in the DLNs of lymphocytes from the circulation. Our findings support a growing number of studies suggesting that in addition to their antimicrobial functions, these cationic peptides may have the capacity to act on cells of the innate and adaptive immune system and regulate their activity. The specific aims of this proposal are to (i) demonstrate the efficacy and safety of small cationic peptides when used as nasal vaccine adjuvants (ii) elucidate the underlying immunological basis for adjuvant activity of cationic peptides.